A-Lipoic Acid Alleviates Folic Acid-Induced Renal Damage Through Inhibition of Ferroptosis.
A-Lipoic Acid Alleviates Folic Acid-Induced Renal Damage Through Inhibition of Ferroptosis.
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A-硫辛酸通过抑制铁凋亡减轻叶酸诱导的肾损伤。
DOI：
10.3389/fphys.2021.680544
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发表时间：
2021
影响因子：
4
通讯作者：
Zhai XY
中科院分区：
文献类型：
--
作者：
Li X;Zou Y;Fu YY;Xing J;Wang KY;Wan PZ;Zhai XY
叶酸（FA）诱导的急性肾损伤（阿基）的特征是氧化还原稳态紊乱，导致大量肾小管坏死和炎症。Α-硫辛酸（LA）作为一种抗氧化剂，已被报道在肾脏保护中发挥重要作用，但其潜在机制仍知之甚少。本研究的目的是探讨LA对FA诱导的肾损伤的保护作用。结果表明，LA可改善FA过量注射所致的肾功能损害和组织病理学损害。此外，FA注射诱导严重的炎症，表现为促炎细胞因子肿瘤坏死因子（TNF）-α和IL-1β的释放增加以及巨噬细胞浸润，这可以通过补充LA来减轻。此外，LA不仅通过上调铁蛋白和膜铁转运蛋白（FPN）的表达来减轻细胞铁超载，还通过增加抗氧化剂谷胱甘肽（GSH）和谷胱甘肽过氧化物酶-4（GPX 4）的水平来减轻活性氧（ROS）的积累和脂质过氧化。更重要的是，我们发现LA补充可以减少由FA引起的末端脱氧核苷酸转移酶dUTP缺口末端标记（TUNEL）阳性肾小管细胞的数量，表明铁凋亡介导的肾小管细胞死亡可能被抑制。进一步的研究表明，补充LA可以逆转介导GSH合成的胱氨酸/谷氨酸反向转运体xCT（SLC 7A 11）表达的降低。此外，机制研究表明，p53激活参与了FA诱导的SLC 7A 11抑制作用，而LA补充可抑制这种抑制作用。以上结果表明，LA对FA所致的肾损伤具有保护作用，其机制主要是通过抑制铁凋亡来实现的。
Folic acid (FA)-induced acute kidney injury (AKI) is characterized by the disturbance of redox homeostasis, resulting in massive tubular necrosis and inflammation. Α-lipoic acid (LA), as an antioxidant, has been reported to play an important role in renal protection, but the underlying mechanism remains poorly explored. The aim of this study is to investigate the protective effect of LA on FA-induced renal damage. Our findings showed that LA could ameliorate renal dysfunction and histopathologic damage induced by FA overdose injection. Moreover, FA injection induced severe inflammation, indicated by increased release of pro-inflammatory cytokines tumor necrosis factor (TNF)-α and IL-1β, as well as infiltration of macrophage, which can be alleviated by LA supplementation. In addition, LA not only reduced the cellular iron overload by upregulating the expressions of Ferritin and ferroportin (FPN), but also mitigated reactive oxygen species (ROS) accumulation and lipid peroxidation by increasing the levels of antioxidant glutathione (GSH) and glutathione peroxidase-4 (GPX4). More importantly, we found that LA supplementation could reduce the number of Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive tubular cells caused by FA, indicating that the tubular cell death mediated by ferroptosis may be inhibited. Further study demonstrated that LA supplementation could reverse the decreased expression of cystine/glutamate antiporter xCT (SLC7A11), which mediated GSH synthesis. What is more, mechanistic study indicated that p53 activation was involved in the inhibitory effect of SLC7A11 induced by FA administration, which could be suppressed by LA supplementation. Taken together, our findings indicated that LA played the protective effect on FA-induced renal damage mainly by inhibiting ferroptosis.
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DOI：
10.1073/pnas.1415518111
发表时间：
2014-11-25
影响因子：
11.1
作者：
Linkermann, Andreas;Skouta, Rachid;Krautwald, Stefan
通讯作者：
Krautwald, Stefan
影响因子：
4.6
作者：
Cho HS;Kim JH;Jang HN;Lee TW;Jung MH;Kim TH;Chang SH;Park DJ
通讯作者：
Park DJ
影响因子：
64.8
作者：
Jiang, Le;Kon, Ning;Li, Tongyuan;Wang, Shang-Jui;Su, Tao;Hibshoosh, Hanina;Baer, Richard;Gu, Wei
通讯作者：
Gu, Wei
影响因子：
5.6
作者：
Krstic J;Galhuber M;Schulz TJ;Schupp M;Prokesch A
通讯作者：
Prokesch A
影响因子：
--
作者：
Li, Xue;Zou, Yu;Zhai, Xiao-Yue
通讯作者：
Zhai, Xiao-Yue